Intermittent Hypoxia and Caffeine in Infants Born Preterm

项目概要/摘要 咖啡因通常用于治疗呼吸模式不成熟的早产儿。我们 记录了持续间歇性血氧水平下降（间歇性缺氧，IH）， 在预产期前约6周停止常规咖啡因治疗（月经后34-35周， PMA）。IH是促炎性的，并且与对患者的认知和脑结构的不良影响有关 患有睡眠呼吸暂停综合症和早产儿呼吸暂停的啮齿动物模型。我们解决两个重要问题 在妊娠≤ 30周出生的婴儿中：1）在34-35周停止常规咖啡因后是否发生IH， 持续42周的PMA会引起损伤，2）这种损伤是否可以通过延长咖啡因治疗来减轻， 42周PMA？创新包括高分辨率连续脉搏血氧仪记录到43周PMA， 定量IH、炎症生物标志物测量和定量磁共振成像（MRI） 和磁共振波谱（MRS）来评估结构性和功能性脑损伤。我们之前的研究证实， 经常发生在停止常规咖啡因后，并且在适当的年龄延长咖啡因治疗 给药减弱IH的程度。我们的假设是，与安慰剂相比，1）咖啡因治疗的婴儿 在34-34周和42周PMA之间，咖啡因组的总体IH暴露量较低，2）咖啡因组的IH暴露量较低， 持续炎症的生物标志物证据，这些效应将通过减少IH暴露介导，3） 咖啡因组具有较少的急性脑损伤的结构、微结构和代谢生物标志物， 通过MRI和MRS确定，这些效应将通过延长的 咖啡因组我们将入组220名PT婴儿。符合条件的受试者最早将在32周PMA时入组， 不再有与不成熟的呼吸模式相关的明显症状。入组后，婴儿将开始连续 脉搏血氧仪记录氧（O2）饱和度。我们将110名婴儿随机分配到10 mg/kg的咖啡因组 从常规咖啡因末次给药后第二天开始，每日两次体重和110至等体积安慰剂 治疗，通常通过34-35周PMA。研究药物将持续至42周PMA，并接受脉冲给药 血氧计记录将持续至43周PMA。将获得两个咖啡因水平，出院前第一个 第二个在家，第二个在家。在研究入组和43-45周PMA完成时，炎症生物标志物 并获得脑部MRI/MRS。数据收集还将包括人口统计学、产后病史、 以及出院和研究完成时的医疗状况。我们的研究结果将提供理由， 随后的研究，以评估与持续性IH相关的长期神经发育结局， 大脑持续成熟的关键时期，以及延长咖啡因治疗的衰减作用。的 获得的知识将建立高度相关和易于翻译的新的成本效益战略， 显著改善妊娠≤ 30周早产儿临床实践和公共卫生。

Project Summary/Abstract Caffeine is routinely used in the treatment of preterm (PT) infants with immature breathing patterns. We have documented persisting intermittent decreases in blood oxygen levels (intermittent hypoxia, IH) after stopping routine caffeine treatment about 6 weeks before the due date (34-35 weeks postmenstrual age, PMA). IH is pro-inflammatory and is associated with adverse effects on cognition and brain structure in patients with sleep apnea syndrome and in rodent models of apnea of prematurity. We address 2 significant questions in infants born at ≤ 30 wks gestation: 1) does IH occurring after stopping routine caffeine at 34-35 wks and persisting to 42 wks PMA cause injury, and 2) can this injury be attenuated by extending caffeine treatment to 42 wks PMA? Innovations include high resolution continuous pulse oximeter recordings to 43 wks PMA to quantify IH, measurement of inflammatory biomarkers, and quantitative magnetic resonance imaging (MRI) and MR spectroscopy (MRS) to assess structural and functional brain injury. Our prior studies confirm that IH occurs frequently after cessation of routine caffeine, and that extended caffeine treatment at age-appropriate dosing attenuates the extent of IH. Our hypotheses are that, compared to placebo, 1) caffeine-treated infants will have lower overall IH exposure between 34-34 and 42 weeks PMA, 2) the caffeine group will have less biomarker evidence of continuing inflammation, and these effects will be mediated by reduced IH exposure, 3) the caffeine group will have less structural, microstructural and metabolic biomarkers of acute brain injury as determined by MRI and MRS, and these effects will be mediated by reduced IH exposure in the extended caffeine group. We will enroll 220 PT infants. Eligible subjects will be enrolled as early as 32 wks PMA, when no longer having overt symptoms related to immature breathing pattern. Enrolled, infants will begin continuous pulse oximeter recordings of oxygen (O2) saturation. We will randomize 110 infants to caffeine at 10 mg/kg body weight twice daily and 110 to equal volume placebo starting the day after last dose of routine caffeine treatment, typically by 34-35 weeks PMA. Study drug will be continued until 42 weeks PMA, and pulse oximeter recordings will continue to 43 wks PMA. Two caffeine levels will be obtained, the 1st before discharge home and the 2nd at home. At study enrollment and completion at 43-45 wks PMA, inflammatory biomarkers and brain MRI/MRS will be obtained. Data collection will also include demographics, postnatal medical history, and medical status at hospital discharge and study completion. Our results will provide the justification for subsequent studies to assess longer term neurodevelopmental outcomes associated with persisting IH during a critical period of continuing brain maturation, and the attenuating effects of extended caffeine treatment. The knowledge gained will establish highly relevant and easily translatable new cost-effective strategies to significantly improve clinical practice and public health in infants born preterm at ≤ 30 wks gestation.